Mn-labelled Beta-cyclodextrin for Melanoma Imaging: A Proof-of-concept Preclinical Study.

Background/aim: As prostaglandin E2 (PGE2) and its receptors (EP2) are over-expressed on tumor cells and microenvironment, radiolabeled cyclodextrins targeting such biomolecules are valuable vector candidates in molecular cancer diagnostics. Using experimental melanoma models, we evaluated the in vivo imaging behavior of novel Manganese-52-labeled (Mn) randomly methylated beta-cyclodextrin ([Mn]Mn-DOTAGA-RAMEB) and compared it with the following well-established tumor-specific probes: melanocortin-1 receptor (MC1-R)-affine [Ga]Ga-DOTA-NAPamide and PGE2 selective [Ga]Ga-DOTAGA-RAMEB cyclodextrin.

Materials And Methods: Post-injection of [Ga]Ga-DOTA-NAPamide, [Ga]Ga-DOTAGA-RAMEB, and [Mn]Mn-DOTAGA-RAMEB into MC1-R positive B16F10 melanoma-bearing mice, tumor radio-pharmaceutical uptake was quantified in vivo and ex vivo using preclinical positron emission tomography (PET) and high-performance gamma counter.

Synthesis and Biological Profiling of Seven Heparin and Heparan Sulphate Analogue Trisaccharides.

Researchers are paying increasing attention to the strongly negatively charged heteropolysaccharides in cells, in the extracellular matrix or in the cell wall. Examples of such molecules are glycosaminoglycans (e.g.

Advancements in Plant-Based Therapeutics for Hepatic Fibrosis: Molecular Mechanisms and Nanoparticulate Drug Delivery Systems.

Chronic liver injuries often lead to hepatic fibrosis, a condition characterized by excessive extracellular matrix accumulation and abnormal connective tissue hyperplasia. Without effective treatment, hepatic fibrosis can progress to cirrhosis or hepatocellular carcinoma. Current treatments, including liver transplantation, are limited by donor shortages and high costs.

Chrysin-loaded calixarene-cyclodextrin ternary drug delivery system inhibits TGF-β and galectin-1 mediated pathways in diabetic liver fibrosis.

This study investigated the efficacy of a new chrysin-loaded calixarene-cyclodextrin ternary drug delivery system (DDS) in reversing liver fibrosis in a mouse model of chronic diabetes. The system was designed to enhance the solubility and bioavailability of chrysin (CHR) and calixarene 0118 (OTX008). Adult male CD1 mice received streptozotocin (STZ) injections to induce diabetes.

Development of Imiquimod-induced HaCaT-THP-1 co-culture for modeling of psoriasis.

Psoriasis is one of the most prevalent and chronic inflammatory disease of the skin, associated with disrupted barrier function. Currently, a widely accepted, generally usable cell culture model has not been developed yet. In the present work, we aimed to establish a co-culture model with human keratinocyte (HaCaT) and human monocyte cells (THP-1) induced by Imiquimod (IMQ), which acts on the TLR7 receptor.

High glucose promotes osteogenic differentiation of human lens epithelial cells through hypoxia-inducible factor (HIF) activation.

Cataract, a leading cause of blindness, is characterised by lens opacification. Type 2 diabetes is associated with a two- to fivefold higher prevalence of cataracts. The risk of cataract formation increases with the duration of diabetes and the severity of hyperglycaemia.

Chrysin Directing an Enhanced Solubility through the Formation of a Supramolecular Cyclodextrin-Calixarene Drug Delivery System: A Potential Strategy in Antifibrotic Diabetes Therapeutics.

Calixarene 0118 (OTX008) and chrysin (CHR) are promising molecules for the treatment of fibrosis and diabetes complications but require an effective delivery system to overcome their low solubility and bioavailability. Sulfobutylated β-cyclodextrin (SBECD) was evaluated for its ability to increase the solubility of CHR by forming a ternary complex with OTX008. The resulting increase in solubility and the mechanisms of complex formation were identified through phase-solubility studies, while dynamic light-scattering assessed the molecular associations within the CHR-OTX008-SBECD system.

Block Synthesis and Step-Growth Polymerization of C-6-Sulfonatomethyl-Containing Sulfated Malto-Oligosaccharides and Their Biological Profiling.

Highly sulfated malto-oligomers, similar to heparin and heparan-sulfate, have good antiviral, antimetastatic, anti-inflammatory and cell growth inhibitory effects. Due to their broad biological activities and simple structure, sulfated malto-oligomer derivatives have a great therapeutic potential, therefore, the development of efficient synthesis methods for their production is of utmost importance. In this work, preparation of α-(1→4)-linked oligoglucosides containing a sulfonatomethyl moiety at position C-6 of each glucose unit was studied by different approaches.

Chrysin-based supramolecular cyclodextrin-calixarene drug delivery system: a novel approach for attenuating cardiac fibrosis in chronic diabetes.

Cardiac fibrosis is strongly induced by diabetic conditions. Both chrysin (CHR) and calixarene OTX008, a specific inhibitor of galectin 1 (Gal-1), seem able to reduce transforming growth factor beta (TGF-β)/SMAD pro-fibrotic pathways, but their use is limited to their low solubility. Therefore, we formulated a dual-action supramolecular system, combining CHR with sulfobutylated β-cyclodextrin (SBECD) and OTX008 (SBECD + OTX + CHR).

Effectiveness of Anthocyanin-Rich Sour Cherry Extract on Gliadin-Induced Caco-2 Barrier Damage.

Several types of gluten-related disorders are known, in which the common starting point is gluten-induced zonulin release. Zonulin results in varying degrees of increased permeability in certain gluten-related disorders but is largely responsible for the development of further pathogenic processes and symptoms. Therefore, it is important to know the barrier-modulating role of individual nutritional components and to what extent the antioxidant substance supports the protection of gliadin-induced membrane damage with its radical scavenging capacity.

Cholesterol-Depletion-Induced Membrane Repair Carries a Raft Conformer of P-Glycoprotein to the Cell Surface, Indicating Enhanced Cholesterol Trafficking in MDR Cells, Which Makes Them Resistant to Cholesterol Modifications.

The human P-glycoprotein (P-gp), a transporter responsible for multidrug resistance, is present in the plasma membrane's raft and non-raft domains. One specific conformation of P-gp that binds to the monoclonal antibody UIC2 is primarily associated with raft domains and displays heightened internalization in cells overexpressing P-gp, such as in NIH-3T3 MDR1 cells. Our primary objective was to investigate whether the trafficking of this particular P-gp conformer is dependent on cholesterol levels.

Insights into recent preclinical studies on labelled cyclodextrin-based imaging probes: Towards a novel oncological era.

As malignancies remain one of the major health concerns worldwide, increasing focus has been centered around the application of cyclodextrins (CDs) in cancer imaging and therapy due to their outstanding inclusion forming capability. Albeit the physicochemical properties of CDs were intensively elucidated, the spread of their clinical application is limited by the relative paucity of knowledge about their pharmacokinetic profile, especially biodistribution. Studies applying fluorescently- CDs, or CD-based MRI contrast agents revealed much about pharmacokinetics and diagnostic applications; however, derivatives labelled with positron emitters seem superior molecular probes in the investigation of the route of CDs in biological niche.

BGP-15 Protects against Doxorubicin-Induced Cell Toxicity via Enhanced Mitochondrial Function.

Doxorubicin (DOX) is an efficacious and commonly used chemotherapeutic agent. However, its clinical use is limited due to dose-dependent cardiotoxicity. Several mechanisms have been proposed to play a role in DOX-induced cardiotoxicity, such as free radical generation, oxidative stress, mitochondrial dysfunction, altered apoptosis, and autophagy dysregulation.

First Synthesis of DBU-Conjugated Cationic Carbohydrate Derivatives and Investigation of Their Antibacterial and Antifungal Activity.

The emergence of drug-resistant bacteria and fungi represents a serious health problem worldwide. It has long been known that cationic compounds can inhibit the growth of bacteria and fungi by disrupting the cell membrane. The advantage of using such cationic compounds is that the microorganisms would not become resistant to cationic agents, since this type of adaptation would mean significantly altering the structure of their cell walls.

Concentration-Dependent Antibacterial Activity of Chitosan on .

The antimicrobial effect of chitosan and synthetic chitosan derivatives has been confirmed on many Gram-positive and Gram-negative bacteria and fungi. The tests were carried out on pathogenic microorganisms, so the mechanism and concentration dependence of the inhibitory effect of chitosan were revealed. We conducted our tests on a probiotic strain, .

Synthesis of an amphiphilic vancomycin aglycone derivative inspired by polymyxins: overcoming glycopeptide resistance in Gram-positive and Gram-negative bacteria in synergy with teicoplanin in vitro.

Gram-negative bacteria possess intrinsic resistance to glycopeptide antibiotics so these important antibacterial medications are only suitable for the treatment of Gram-positive bacterial infections. At the same time, polymyxins are peptide antibiotics, structurally related to glycopeptides, with remarkable activity against Gram-negative bacteria. With the aim of breaking the intrinsic resistance of Gram-negative bacteria against glycopeptides, a polycationic vancomycin aglycone derivative carrying an n-decanoyl side chain and five aminoethyl groups, which resembles the structure of polymyxins, was prepared.

In vivo assessment of tumor targeting potential of Ga-labelled randomly methylated beta-cyclodextrin (RAMEB) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) using positron emission tomography.

Cyclodextrin derivates (CyDs) can form complexes with cyclooxygenase-2 induced tumor promoting prostaglandin E2 (PGE2). Based on our previous observations, Ga-labelled CyDs may represent promising radiopharmaceuticals in the positron emission tomography (PET) diagnostics of PGE2 positive tumors. We aimed at evaluating the tumor-targeting potential of Ga-NODAGA conjugated randomly methylated beta-cyclodextrin (Ga-NODAGA-RAMEB) and 2-hydroxypropyl-β-cyclodextrin (Ga-NODAGA-HPβCD) using in vivo PET imaging with experimental tumor models.

Effects of Hydroxypropyl-Beta-Cyclodextrin on Cultured Brain Endothelial Cells.

The application of 2-hydroxypropyl-beta-cyclodextrin (HPBCD) in the treatment of the rare cholesterol and lipid storage disorder Niemann-Pick disease type C opened new perspectives in the development of an efficient therapy. Even if the systemic administration of HPBCD was found to be effective, its low permeability across the blood-brain barrier (BBB) limited the positive neurological effects. Nevertheless, the cellular interactions of HPBCD with brain capillary endothelial cells have not been investigated in detail.

The epigenetic state of IL-4-polarized macrophages enables inflammatory cistromic expansion and extended synergistic response to TLR ligands.

Prior exposure to microenvironmental signals could fundamentally change the response of macrophages to subsequent stimuli. It is believed that T helper-2 (Th2)-cell-type cytokine interleukin-4 (IL-4) and Toll-like receptor (TLR) ligand-activated transcriptional programs mutually antagonize each other, and no remarkable convergence has been identified between them. In contrast, here, we show that IL-4-polarized macrophages established a hyperinflammatory gene expression program upon lipopolysaccharide (LPS) exposure.

Enhanced Antioxidant and Anti-Inflammatory Effects of Self-Nano and Microemulsifying Drug Delivery Systems Containing Curcumin.

Turmeric has been used for decades for its antioxidant and anti-inflammatory effect, which is due to an active ingredient isolated from the plant, called curcumin. However, the extremely poor water-solubility of curcumin often limits the bioavailability of the drug. The aim of our experimental work was to improve the solubility and thus bioavailability of curcumin by developing self-nano/microemulsifying drug delivery systems (SN/MEDDS).

In vivo investigation of Gallium-68 and Bismuth-205/206 labeled beta cyclodextrin for targeted alpha therapy of prostaglandin E2 receptor-expressing tumors in mice.

Prostaglandin E2 (PGE2) molecule and its receptors play an important role in the development of malignancies and metastases therefore PGE2 may play a crucial role in the diagnosis and a new therapeutic target in the field of radionuclide therapy of PGE2-positive tumors. PGE2 form complexes with RAMEB (randomly-methylated-beta-cyclodextrin) with high affinity therefore the aim of this present study was to synthesize a PGE2-specific DOTAGA-RAMEB, which can be labeled with diagnostic and therapeutic isotopes also and binds to PGE2-positive tumors. DOTAGA-RAMEB was labeled with Ga and Bi radionuclides and their radiochemical purity (RCP%), partition coefficient (logP values), and in vitro and in vivo stability were determined.

Stability, Permeability and Cytotoxicity of Buccal Films in Allergy Treatment.

Oral mucoadhesive systems, such as polymer films, are among innovative pharmaceutical products. These systems can be applied in swallowing problems and can also be used in geriatrics and paediatrics. In our earlier work, we successfully formulated buccal mucoadhesive polymer films, which contained cetirizine-hydrochloride (CTZ) as the API.

Comparison of the Modulating Effect of Anthocyanin-Rich Sour Cherry Extract on Occludin and ZO-1 on Caco-2 and HUVEC Cultures.

Increased permeability of the epithelial and endothelial cell layers results in the onset of pathogenic mechanisms. In both cell types, cell-cell connections play a regulatory role in altering membrane permeability. The aim of this study was to investigate the modulating effect of anthocyanin-rich extract (AC) on TJ proteins in inflammatory Caco-2 and HUVEC monolayers.

Effects of the Calix[4]arene Derivative Compound OTX008 on High Glucose-Stimulated ARPE-19 Cells: Focus on Galectin-1/TGF-β/EMT Pathway.

Diabetic retinopathy (DR) is a neurovascular disease characterized by the reduction of retina integrity and functionality, as a consequence of retinal pigment epithelial cell fibrosis. Although galectin-1 (a glycan-binding protein) has been associated with dysregulated retinal angiogenesis, no evidence has been reported about galectin-1 roles in DR-induced fibrosis. ARPE-19 cells were cultured in normal (5 mM) or high glucose (35 mM) for 3 days, then exposed to the selective galectin-1 inhibitor OTX008 (2.

Investigation of the Drug Carrier Properties of Insoluble Cyclodextrin Polymer Microspheres.

The investigation of the usability of solid insoluble β-cyclodextrin polymers (βCDP) in micro-sized, controlled drug delivery systems has only recently attracted interest. Our aim was to form complexes with poorly soluble active pharmaceutical ingredients (APIs) with two types of βCDP for drug delivery applications. Solid insoluble cyclodextrin polymer of irregular shape (βCDPIS) and cyclodextrin microbeads (βCDPB) were used in the experiments.